Follow-on Versions Research Articles

Relevance of distinctions and parallels between the US and EU guidelines for determination of comparative effectiveness and safety of the orally inhaled drug products

Approval of drug products for market registration warrants, among other data, evidence to support their safety and effectiveness in the target populations. The extent of investigations to provide the supporting evidence varies between the new innovator products and their follow-on versions generally referred to as Generic Drugs Products in the United States and Hybrids in the Europe. The new drug applications entail large data sets encompassing both nonclinical and clinical product developments. Safety and effectiveness in man is studied in sequentially phased clinical trials, including post marketing evaluations (Where applicable). However, for the generic/hybrid products the safety and effectiveness are established through determination of bioequivalence in head-to-head comparison between the originator and the follow-ons. Methods for documentation of bioequivalence for drug products that reach target site(s) through systemic circulation are aligned worldwide. However, establishing bioequivalence of orally inhaled drug products is complex as drug delivery to the local site(s) of action is independent of the systemic circulation. Documentation of bioequivalence gets further complicated due to the Drug-Device combination nature of these products. The guidelines for establishment of BE of locally acting orally inhaled drugs products vary among certain geographies. This article examines the scientific underpinning of distinctions and similarities between the US and EU guidelines.

A Comparative Study on Approval of Follow-on Version of Sevelamer Carbonate and Glatiramer Acetate (GA) in US, EU

Abstract: Many non-biological drugs, different in terms of their structure and mode of action, pharmacological classification, and therapeutic indication, have a common factor of structural complexity and are grouped as non-biological complex drugs (NBCDs). When an innovator drug nears the time of off-patent, different manufacturers attempt to produce its subsequent version, so the patients will have a cost-effective therapeutic equivalent. Since the innovator molecule is complex, its follow-on drug can be called its true generic version, if its bioavailability, bioequivalence and therapeutic equivalence to the innovator drug are demonstrated. However, it is observed that a case-to-case basis approach is implemented by European Medicines Agency (EMA) and Food and Drug Administration, US (USFDA) in the approval of such drugs and there is no uniformity observed between the two. : In this study, an attempt is made to study the complexity of molecules compare and understand the data requirements, and procedures adopted for the review and approval of such complex products. Therefore, drug sevelamer carbonate and glatiramer acetate are selected for the study. A methodical approach was followed. European assessment reports and drug approvals available in the orange book database of the former two regulatory agencies were studied. It is observed that the generic version of glatiramer acetate is approved as an abbreviated new drug application (ANDA) by Food and Drug Administration whereas the same was approved as the hybrid application by European Medicines Agency requiring the applicant to generate and submit more data. Thus, harmonization of the regulatory requirements for the approval of follow-on versions of such complex drugs is essential for better understanding, predictability of the regulatory process, and acceleration of the drug approval process, in the interest of patients. This will help the faster access of the drugs to the patients and allow interchangeability of the innovator drugs with its cost-effective generic version.

Regulatory considerations for generic products of non-biological complex drugs.

The Non-Biological Complex Drug (NBCD) Working Group defines an NBCD as "a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by physicochemical analytical means". There are concerns about the potential clinical differences between the follow-on versions and the originator products and within the individual follow-on versions. In the present study, we compare the regulatory requirements for developing generic products of NBCDs in the European Union (EU) and the United States (US). The NBCDs investigated included nanoparticle albumin-bound paclitaxel (nab-paclitaxel) injections, liposomal injections, glatiramer acetate injections, iron carbohydrate complexes, and sevelamer oral dosage forms. The demonstration of pharmaceutical comparability between the generic products and the reference products through comprehensive characterization is emphasized for all product categories investigated. However, the approval pathways and detailed requirements in terms of non-clinical and clinical aspects may differ. The general guidelines in combination with product-specific guidelines are considered effective in conveying regulatory considerations. While regulatory uncertainties still prevail, it is anticipated that through the pilot program established by the European Medicines Agency (EMA) and the FDA, harmonization of the regulatory requirements will be achieved, thereby facilitating the development of follow-on versions of NBCDs.

Medication practice in hospitals: are nanosimilars evaluated and substituted correctly?

Introduction: This study investigates the drug selection and dispensing behaviour of hospital pharmacists of intravenous iron products including iron sucrose and iron sucrose similar, with special emphasis on substitution and interchangeability in France and Spain. Iron– carbohydrate complex drugs represent different available intravenous iron drugs and are part of the non-biological complex drug (NBCD) class, an expanding drug class with up to 30 brands available in intravenous pharmacotherapy and over 50 in clinical development. Follow-on versions of iron sucrose have appeared in some markets such as France and Spain, which were authorised by the generic approval pathway. However, differences in clinical efficacy and safety of iron sucrose similars compared with the reference originator drug Venofer have been observed, putting a question mark on their equivalence as assessed for authorisation and consequently their substitutability and interchangeability. Method: 70 French and 70 Spanish hospital pharmacists were surveyed via an online questionnaire on their formulary selection and dispensing behaviour of intravenous iron medicines. Results: There is little awareness about the characteristics of this class of drugs and the reported differences in safety and efficacy between iron sucrose and iron sucrose similars. In approximately 85% of cases the intravenous iron is chosen according to the hospital formulary. In 30% (France) and 34% (Spain) of cases an iron sucrose similar was dispensed because the formulary requires dispensing an alternative lower cost drug when available. In 26% (France) and 52% (Spain) of cases the physician is not informed on such a medication change using a similar product. Conclusions: Evaluation of NBCD similars for substitution and interchange by hospital pharmacists is rarely based on scientific and clinical criteria but rather on cost aspects only, which does not ensure safe, efficacious and cost-effective use of such drugs.

Influence of Production Process and Scale on Quality of Polypeptide Drugs: a Case Study on GLP-1 Analogs.

Manufacturing processes for polypeptide/protein drugs are designed to ensure robust quality, efficacy and safety. Process differences introduced by follow-on manufacturers may result in changes in quality and clinical outcomes. This study investigated the impact of production methods on the stability and impurities of liraglutide and semaglutide drug substances/products, and the potential impact on drug quality, efficacy and safety. State-of-the-art analytical methods were used to compare physical and chemical stability, and impurity profiles of drug substances/products from different suppliers. Identified polypeptide-related impurities were evaluated for immunogenicity potential by in silico T cell epitope prediction. Semaglutide immunogenicity in clinical trials (SUSTAIN) was evaluated using a tiered antibody analysis. Manufacturing scale and process strongly impacted the physical stability of the products. Trace metals increased high-molecular-weight protein formation for liraglutide and semaglutide. Synthetic and recombinant liraglutide produced by five suppliers had distinct impurity profiles compared with the originator. In silico evaluation suggested that new impurities could be immunogenic. Immunogenicity of semaglutide in clinical trials was lower than for liraglutide. Differences in manufacturing processes affect chemical/physical stability and impurity profile, and may impact immunogenicity. Follow-on versions of liraglutide and semaglutide, and possibly other polypeptides, should be clinically evaluated for efficacy and safety.

Nanomedicines in clinical practice: Are colloidal iron sucrose ready-to-use intravenous solutions interchangeable?

The assessment of interchangeability of nanomedicines and nanosimilars is required for ensuring the safety, quality and efficacy of these complex drugs. Since 2011, regulatory agencies and researchers focused their attention on the characterization of iron sucrose, a colloidal solution parenterally used for the treatment of iron deficiency anemia, as well as on their follow-on versions, the so-called iron sucrose similars (ISSs).The purpose of this study was the evaluation of the size and size distribution of both IS and ISSs after dilution in polypropylene bags containing saline, mimicking the preparation of ready-to-use infusions to be administered in a hospital environment. The assays were carried out for 72 h, determining a general stability of the colloidal solutions investigated. Nevertheless, a dissimilar size and size distribution but also different visual appearance of IS and ISSs were recorded when the drugs diluted for therapeutic use. These results agree with previously published physicochemical and clinical data supporting the lack of exchangeability between IS and ISSs.

Ion quantification in liposomal drug products using high performance liquid chromatography

A simple, straightforward analytical method based on liquid chromatography has been optimized to quantify total, internal, and external ions in drug-loaded liposomal products. The quantification of ammonium and sulfate ions in Doxil is detailed; although, the methodology has been extrapolated to quantitate a variety of ions, including calcium, acetate, and others in several different liposomal formulations. Total ion concentrations were measured after disruption of the liposome via lyophilization, to liberate all components. External ion concentrations were made following membrane centrifugation, without disruption of the liposome structure, where the permeate fraction was analyzed for external ion quantities. The internal ion fraction was derived from mass balance of the total and external ion measurements. High performance liquid chromatography (HPLC), equipped with different separation columns, and coupled to a charged aerosol detector, was employed for all ion quantifications. The analytical measurements were confirmed using simple stoichiometry based on the drug crystallization of doxorubicin within the liposome interior. The method presented herein is quick, highly accurate, and has significantly improved lower limits of detection and quantification over other traditional methods. As more follow-on versions of Doxil are being developed, this facile approach to ion quantitation can be used to help establish compositional similarity to the reference listed drug.

Regulatory challenges of nanomedicines and their follow-on versions: A generic or similar approach?

Nanomedicines and follow-on versions (also called nanosimilars in the EU) have been on the market partially for decades although without recognition of their nano properties in the beginning; a substantial number is in clinical development. Nanomedicines are typically synthetic and belong to the non-biological complex drugs. They show a high variability in form, structure, and size. Additionally large molecule biologics show nano-characteristics meaning nano-dimension in size (1-100 nm) or specific properties related to these dimensions. The high complexity of nanomedicines with their heterogeneous structures do not allow a full physicochemical quality characterization, challenging the regulatory evaluation especially for follow-on versions upon comparison with the reference product. The generic paradigm with the sameness approach for quality and bioequivalence in blood plasma is not appropriate for nanomedicines where a similar approach is needed. After experiencing non-equivalence of authorized parenteral colloidal iron follow-on versions, EMA and FDA issued reflection papers and draft guidances for industry to present their current thinking on the evaluation of such complex products. A stepwise approach to evaluate the extent of similarity, from quality, including critical quality attributes (CQA) and assessment of nano properties, to a non-clinical biodistribution assay, required in the the EU but not in the US, and to clinical evaluation makes sense. The cumulated totality of evidence for the authorization of nanomedicine follow-on versions goes case-by-case. Interchangeability, or substitutability, is a challenge. However, a defined or even harmonized approval pathway for these follow-versions is still missing and causes potential differences in approval. To progress, a science-based discussion platform among stakeholders and experts in the field is necessary. An agenda has been agreed [5], namely CQA assessment, publication of scientific and clinical findings, consensus on nomenclature and labelling, and regulatory actions on substandard complex drug products. Consensus created in a public private approach will support progress towards a defined and harmonized regulatory pathway for nanomedicines and their follow-on versions. This will provide drug innovation but also larger access to follow-on versions of nanomedicines, both a benefit for the patient.

A robust and easily reproducible protocol for the determination of size and size distribution of iron sucrose using dynamic light scattering

Iron sucrose (IS), a nanocolloidal solution used in the treatment of iron deficiency anemia, is currently under investigation for the elucidation of its critical quality attributes. Assessment of IS’s size and size distribution has been recently attempted using dynamic light scattering (DLS). However, due to heterogeneous interpretation of DLS data, variable results were retrieved. The aim of this work was to establish a simple and reproducible DLS protocol to unequivocally define the size and size distribution of IS by using size distribution approximation in Number. Underlining the limitations of the commonly used DLS approximations, we identified the drug as being composed of a population of monodisperse nanoparticles of about 7 nm in diameter. The method here described might therefore be useful for the evaluation of quality, safety and efficacy of IS and its follow-on versions.

Equivalence of complex drug products: advances in and challenges for current regulatory frameworks

Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified.

Medication practice in hospitals: are nanosimilars evaluated and substituted correctly?

IntroductionThis study investigates the drug selection and dispensing behaviour of hospital pharmacists of intravenous iron products including iron sucrose and iron sucrose similar, with special emphasis on substitution and interchangeability...

Non-biological complex drugs (NBCDs) and their follow-on versions: time for an editorial section

Non-biological complex drugs (NBCDs) and their follow-on versions: time for an editorial section

An integrated assessment of morphology, size, and complement activation of the PEGylated liposomal doxorubicin products Doxil®, Caelyx®, DOXOrubicin, and SinaDoxosome

In order to improve patient's benefit and safety, comprehensive regulatory guidelines on specificities of Non-Biological Complex Drugs (NBCDs), such as doxorubicin-encapsulated liposomes, and their follow-on versions are needed. Here, we compare Doxil® and its European analog Caelyx® with the two follow-on products DOXOrubicin (approved by the US Food and Drug Administration) and SinaDoxosome (produced in Iran) by cryogenic transmission electron microscopy, dynamic light scattering and Nanoparticle Tracking Analysis, and assess their potential in activating the complement system in human sera. We found subtle physicochemical differences between the tested liposomal products and even between the tested batches of Doxil® and Caelyx®. Notably, these included differences in vesicular population aspect ratios and particle number. Among the tested products, only SinaDoxosome, in addition to the presence of unilamellar vesicles with entrapped doxorubicin crystals, contained empty circular disks. Differences were also found in complement responses, which may be related to some morphological differences. This study has demonstrated an integrated biophysical and immunological toolbox for improved analysis and detection of physical differences among vesicular populations that may modulate their clinical performance. Combined, these approaches may help better product selection for infusion to the patients as well as for improved design and characterization of future vesicular NBCDs with enhanced clinical performance and safety.

Russian nuclear forces, 2015

Russia is modernizing its strategic and nonstrategic nuclear warheads. It currently has 4,500 nuclear warheads, of which roughly 1,780 strategic warheads are deployed on missiles and at bomber bases. Another 700 strategic warheads are in storage along with roughly 2,000 nonstrategic warheads. Russia deploys an estimated 311 ICBMs that can carry approximately 1,050 warheads. It is in the process of retiring all Soviet-era ICBMs and replacing them with new systems, a project that according to Moscow is about halfway complete. The outgoing ICBMs will be replaced by the SS-27 Mod. 1 (Topol-M), the SS-27 Mod. 2, two follow-on versions of the SS-27 which are still in development, and a new liquid-fuel “heavy” ICBM. Following technical problems, the Russian Navy is also rolling out its new Borey-class nuclear-powered ballistic missile submarine. Russia’s upgrades to its nuclear arsenal help justify modernization programs in other nuclear weapon states, and raise questions about Russia's commitment to its obligations under the nuclear Non-Proliferation Treaty to reduce and eliminate nuclear weapons.

The authorization of non-biological complex drugs (NBCDs) follow-on versions: specific regulatory and interchangeability rules ahead?

Author byline as per print journal: Professor Stefan Mühlebach, PhD, Professor Arnold Vulto, PharmD, PhD, Jon SB de Vlieger, PhD, Vera Weinstein, PhD, Beat Flühmann, PhD, Vinod P Shah, PhD Introduction: Besides biologicals, a new class of complex drugs – non-biological complex drugs (NBCDs), e.g. liposomes, iron

How to Regulate Nonbiological Complex Drugs (NBCD) and Their Follow-on Versions: Points to Consider

The aim of this critical review is to reach a global consensus regarding the introduction of follow-on versions of nonbiological complex drugs (NBCD). A nonbiological complex drug is a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by state of the art physicochemical analytical means and where the clinical meaning of the differences is not known. The composition, quality and in vivo performance of NBCD are highly dependent on manufacturing processes of both the active ingredient as well as in most cases the formulation. The challenges posed by the development of follow-on versions of NBCD are illustrated in this paper by discussing the 'families' of liposomes, iron-carbohydrate ('iron-sugar') drugs and glatiramoids. It is proposed that the same principles for the marketing authorization of copies of NBCD as for biosimilars be used: the need for animal and/or clinical data and the need to show similarity in quality, safety and efficacy. The regulatory approach of NBCD will have to take into consideration the specific characteristics of the drugs, their formulation and manufacturing process and the resulting critical attributes to achieve their desired quality, safety and efficacy. As with the biosimilars, for the NBCD product, family-specific methods should be evaluated and applied where scientifically proven, including sophisticated quality methods, pharmacodynamic markers and animal models. Concerning substitution and interchangeability of NBCD, it is also advisable to take biosimilars as an example, i.e. (1) substitution without the involvement of a healthcare professional should be discouraged to ensure traceability of the treatment of individual patients, (2) keep an individual patient on a specific treatment if the patient is doing well and only switch if unavoidable and (3) monitor the safety and efficacy of the new product if switching occurs.

English

Introduction Therapeutic proteins are next-generation drugs in the prevention and treatment of diseases, in particular human critical illness. The expiration of patents in the originally approved biopharmaceutics has stimulated a great excitement and the subsequent development of “followon” versions of these first-in-line biotherapeutic products, known as “Biosimilars” or “Biobetters”. Biosimilars are a new class of drugs intended to offer comparable safety and efficacy (or clinical equivalence) to their original reference products which are brand name drugs and no longer under patent coverage. However, preparing exact copies of biologicals is much more challenging than replicating small molecules due to their structural complexity, intricate manufacturing processes and their potential risks for increased immunogenicity. Therefore, specific regulatory approval pathways and guidelines must be followed when creating Biosimilars. This article reviews the requirements and key considerations for producing Biosimilar agents as well as the important Biosimilar guidelines/regulations from different countries including the World Health Organization, Food and Drug Administration and the European Medicines Agency. Conclusion Patents that expired or are soon to expire have provided a great opportunity for companies to make copies or ‘generic’ versions of these drugs. Despite some challenges, therapeutic development of lower cost Biosimilars will inevitably enter the drug market in the near future, increasing the market competition and patients’ access to the more cost-effective therapies that they may not have otherwise. Introduction The continuous clinical and commercial success of biologics such as monoclonal antibodies (mAb) and recombinant versions of endogenous proteins is transforming the pharmaceutical industry. Protein drugs have been demonstrated to significantly alter and even possibly “cure” some human critical illness where synthetic small molecule agents have failed1. In 2010, worldwide sales of all biologics approached nearly the $100 billion mark in 20122 and it is expected that more than 50% of new drug approvals will be biologics3 by 2015, rising to more than 70% by 20254. As these drugs begin to come off patent, substantial opportunities exist for other companies to make copies or ‘generic’ versions of these drugs, now commonly known as “Biosimilars” or “Biobetters”. As of the end of 2012, there are a total of 17 Biosimilar and/or Biobetter recombinant protein therapeutics on the market in Europe alone (Table 1). However, the introduction of follow-on versions of biological products is much more difficult than for small molecules. Many biologicals such as mAb and recombinant therapeutic proteins are much larger and more complex, the extent to which * Corresponding authors Emails: mingyuehe2001@yahoo.com; drcarledwards@gmail.com 1 Laboratory of Recombinant Protein Therapeutics, Chengdu Institute of Biological Products, Chengdu 610041, PR China 2 Department of Dermatology, University of Colorado at Denver, Anschutz, Medical Centre, Aurora, CO 80025, USA 3 National Key Laboratory of Biotherapy and Cancer Research, Western Sichuan China Medical School and Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China Table 1 Biosimilar approved in Europe Branded product Biosimilar manufacturer

TCH-012 Differences in Purity Between Biosimilar Filgrastims and Copy Biological Filgrastims

Background Biosimilars are follow-on versions of peptide biological drugs, and differences in manufacturing and formulation can result in variations in physicochemical and clinical profiles. The European Medicines Agency (EMA) has...

Scientific considerations for complex drugs in light of established and emerging regulatory guidance

On March 9, 2012, the New York Academy of Sciences brought together experts representing a variety of perspectives--including academic, industrial, regulatory, as well as those from physicians and consumers--to discuss considerations for the non-biological complex drug (NBCD) regulatory approval pathway, given the emerging regulatory guidelines for biosimilars (follow-on biological complex drugs). Some of the organizers of the conference expressed their belief that NBCDs share a number of characteristic features with biologicals: the structure cannot be fully defined by the available (physicochemical) analytical tests, and quality assurance is based on in-depth knowledge, consistency, and control of the production process. However, their view on NBCDs was not universally accepted among the experts who participated in the conference. Plenary sessions addressed the most recent regulatory developments, experimental design, interchangeability, and immunogenicity issues for follow-on versions of complex drugs from the perspective of key audiences, including industry, regulatory agencies, physicians, and consumers. This report summarizes these various perspectives on NBCDs and the scientific and regulatory considerations associated with complex drug categories.

Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars

Biologics such as monoclonal antibodies are much more complex than small-molecule drugs, which raises challenging questions for the development and regulatory evaluation of follow-on versions of such biopharmaceutical products (also known as biosimilars) and their clinical use once patent protection for the pioneering biologic has expired. With the recent introduction of regulatory pathways for follow-on versions of complex biologics, the role of analytical technologies in comparing biosimilars with the corresponding reference product is attracting substantial interest in establishing the development requirements for biosimilars. Here, we discuss the current state of the art in analytical technologies to assess three characteristics of protein biopharmaceuticals that regulatory authorities have identified as being important in development strategies for biosimilars: post-translational modifications, three-dimensional structures and protein aggregation.